Spermicidal vaginal pharmaceutical concentrate for producing nonaqueous foam with aerosol propellants



United States Patent 3,384,541 SPERMICIDAL VAGINAL PHARMACEUTICALCONCENTRATE FOR PRODUCENG NON- AQUEOUS FOAM WITH AEROSOL PROPEL- LANTSWilliam G. Clark, 1142 Las Pulgas Road, Pacific Palisades, Calif. 90272No Drawing. Filed Oct. 28, 1964, Ser. No. 407,231 1 Claim. (Cl. 167-58)ABSTRACT OF THE DISCLOSURE The invention provides a new composition ofmatter comprising a major proportion of propylene glycol in a minorproportion of an ethoxylated tallow alcohol, the composition beingadapted to incorporation in foam-producing assemblies.

This invention relates to a new and useful non-aqueous foam-producingpharmaceutical substance, and more particularly to such a substanceadapted for use as a medicant in a self-propelled dispenser usingfluorinated hydrocarbons or other aerosol propellants.

There is a need for a simple, easily used single-dose contraceptivewhich can be applied as an aerosol foam into the vaginal canal. Therehas also been a need for a pharmaceutical vehicle for medicants adaptedto be injected into human body cavities that can be used either with orwithout water, depending upon the stability of the ingredients to beincorporated into the preparation. Thus, it is desirable to have asingle base that can be used with various enzymes, antibiotics, andmedicinal agents, with or without spermicidal agents.

Accordingly, it is a primary object of the present invention to providea newand useful non-aqueous foamproducing vehicle.

Another object of the invention is to provide a vehicle of the typedescribed in combination with spermicidal substances.

Another object of the present invention is to provide a foam-producingvehicle that can be used either with or without water and variousenzymes, antibiotics, and spermicidal agents.

Yet another object .of the present invention is to provide a new anduseful non-aqueous foam-producing vehicle which contains ethoxylatedtallow alcohol as a foaming agent, emulsifier, detergent, Wetting agent,and viscosity builder.

A further object of the present invention is to provide a vehicle of thetype described which is also spermicidal.

A still further object of the present invention is to provide a vehicleof the type described which is especially suited for use in and incombination with aerosol type applicators for injecting medicants intohuman body cavities.

A medicinal application of this type is shown and claimed in copendingapplication Ser. No. 407,170, filed Oct. 28, 1964, by the instantinventor, now abandoned.

The non-aqueous foam-producing pharmaceutical substance of the presentinvention includes a vehicle containing ethoxylated tallow alcohol as afoaming agent, emulsifier, detergent, wetting agent, and viscositybuilder. The

3,384,541 Patented May 21, 1968 "ice ethoxylated alcohol is a condensateof pressure-hydrogenated tallow alcohol. The general formula is with Rbeing a combination of CH (CH CH OH (stearyl alcohol 62%), CH (CH CH OH(cetyl alcohol 33%), and CH (CH CH OH (myristyl alcohol 5%) and the xranging from three to eleven moles of ethylene oxide.

Propylene glycol U.S.P. may serve as a solvent, preservative, andemollient, and propylhydroxyparaben U.S.P. and methylhydroxyparabenU.S.P. are used as preservatives. In preparing the vehicle, grams ofpropylene glycol U.S.P'. are heated to approximately 50 degrees C. and0.4 gram of methylhydroxyparaben plus 0.2 grain of propylhydroxyparabenare added and stirred. Two grams of ethoxylated tallow alcoholcontaining three moles of ethylene oxide, oil-soluble type, are heatedto 50 degrees C., and combined with the propylene glycol preservativecombination. Ethoxylated tallow alcohol containing from three to elevenmoles of ethylene oxide may be used in this formula, depending upon theconsistency of foam desired. The product is allowed to cool, and asufficient amount of propylene glycol U.S.P. is added to make theproduct weigh 50 grams. Other glycols, as well as glycerol can be usedin place of propylene glycol.

Spermicidal preparations are made from this vehicle, as described in thefollowing examples, by dissolving the active ingredients in a sufiicientamount of propylene glycol U.S.P. to make 50 grams, and the resultingproduct is combined with 50 grams of the vehicle to make grams ofspermicidal foam concentrate. In some cases, heat must be employed toeffect solution. Heat labile substances must be added after cooling.

The non-ionic nature of the vehicle makes possible the addition ofcationic or anionic substances without affecting the foam-producing andbarrier action of the ingredients. Propylene glycol is an excellentsolvent for many organic chemicals. Its solubility with water in allproportions makes possible the addition of aqueous solutions ofspermicidal agents. This vehicle mixes quickly with seminal fluid andvaginal secretions, permitting rapid action of the active ingredients.Its surfactant action spreads the spermicide into all surfaces andcrevices. The non-aqueous nature of the vehicle minimizes variations inaction due to individual variations of moisture present. The viscousbase and foam provide barrier action to passage of sperm through thecervix.

The vehicle itself is spermicidal as shown by the Sanderson-Cramermethod of spermicidal evaluation. The vehicle, when diluted with twoparts of buffered fructose solution, kills human sperm in twentyseconds. The buffered fructose solution contained three percentfructose, 0.24% anhydrous phosphate, 0.01% mono potassium phosphate,0.2% sodium chloride, and distilled water (q.s.).

When diluted with an equal volume of propylene glycol U.S.P., thevehicle of the present invention produces a foam with propellants froman aerosol container of the types shown and described in said copendingapplication. A partial emulsification results when the foam concentrateis shaken with fluorinated hydrocarbons or other aerosol propellants.When released in the manner described in said copending application, anexcellent foam is produced. The ratio of vehicle to added propyleneglycol can be altered to vary the foam consistency or to compensate forviscosities of added substances. Because of the insolubility of theethoxylated tallow alcohols in water, the latter can be added to stiffenthe foam where it does not affect the stability of added substances.

The formulation has been shown to be non-toxic to the mucosa of thehuman vagina and cervix. An amount in excess of that ordinarily used,namely grams of the liquid foam concentrate, was applied to the cervicalmucosa of six oflice patients and examination made the next morning. Noindications of inflammation were seen, even on repeated application.

The vehicle of the present invention is stable over long periods of timeand maintains the stability of added ingredients which are unstable inaqueous vehicles of the prior art.

The following are typical examples of the non-aqueous foam-producingpharmaceutical substance of the present invention:

EXAMPLE 1 EXAMPLE 2 The product of Example 1 was prepared in the mannerof Example 1 except that the ethoxylated tallow alcohol contained fourmoles of ethylene oxide.

EXAMPLE 3 The product of Example 1 was prepared in accordance with thesteps of Example 1 except that the ethoxylated tallow alcohol containedfive moles of ethylene oxide.

EXAMPLE 4 The product of Example 1 was prepared in accordance with thesteps of Example 1 except that the ethoxylated tallow alcohol containedsix moles of ethylene oxide.

EXAMPLE 5 The product of Example 1 was prepared in accordance with thesteps of Example 1 except that the ethoxylated tallow alcohol containedseven moles of ethylene oxide.

EXAMPLE 6 The product of Example 1 was prepared in accordance with thesteps of Example 1 except that the ethoxylated tallow alcohol containedeight moles of ethylene oxide.

EXAMPLE 7 The product of Example 1 was prepared in accordance with thesteps of Example 1 except that the ethoxylated tallow alcohol containednine moles of ethylene oxide.

EXAMPLE 8 The product of Example 1 was prepared in accordance with thesteps of Example 1 except that the ethoxylated tallow alcohol containedten moles of ethylene oxide.

EXAMPLE 9 The produce of Example 1 was prepared in accordance with thesteps of Example 1 except that the ethoxylated tallow alcohol containedeleven moles of ethylene oxide.

EXAMPLE 10 A product was prepared in accordance with each of thepreceding examples except that, in each case, eighty grams 1 of glycerolUSP were used in place of the propylene glycol.

EXAMPLE 11 Grams Aliphatic polyoxyethylene ether (100% active.

Made from commercial tridecyl alcohol and ethylene oxide to givematerial with an inverse cloud point of approximately 40-42 C. Thematerial is made by standard ethoxylation technique) 5 The vehicle ofExample 1 50 Propylene glycol q.s. ad 100 The aliphatic polyoxyethyleneether provides an excellent spermicide. Its non-ionic nature permits itscombination with anionic or cationic agents without any change inspermicidal or antibiotic power. This composition produces an excellentfoam when combined with propellants in aerosol containers. The ratio ofpropylene glycol to vehicle can be altered to produce varied consistencyof foam.

EXAMPLE 12 Grams Aliphatic polyoxyethylene ether (100% active, de-

scribed in Example 11) 5 Lactic acid U.S.P. 0.5 Distilled water 10Vehicle of Example 1 50 Propylene glycol U.S.P. q.s. ad

Sufiicient acid has been added to this product to produce a pH of 4.0which increases the spermicidal power because it produces a conditionresembling the vaginal pH of 4.5. Water has been added to aid in theionization of the acid because the effect of acids in spermicidesdepends upon the extent to which they ionize.

EXAMPLE 13 Grams Aliphatic polyoxyethylene ether (100% active, de-

scribed in Example 11) 5 Papain 1 Vehicle of Example 2 50 Propyleneglycol U.S.P. q.s. ad 100 EXAMPLE 14 Grams Aliphatic polyoxyethyleneether (100 active, de-

scribed in Example 11) 5 Trypsin 1 Vehicle of Example 3 50 Propyleneglycol U.S.P. q.s. ad 100 Other pancreatic enzymes that could be used inthe foam concentrate include cathepsins and chymotrypsin.

EXAMPLE l5 Grams Aliphatic polyoxyethylene ether of Example 11 5Desoxyribonucleases (a Dornase proteolytic enzyme) 1 Vehicle of Example4 50 Propylene glycol U.S.P. q.s. ad 100 Bacterial protease from B.Subtz'lis 1 Vehicle of Example 5 50 Propylene glycol U.S.P. q.s. ad 100Other proteases from microbiological sources included those fromPseudomonas, Clostridia, and fungi. Hyaluronidase also has been used.The proteolytic enzymes described in Examples 13 through 16 enhance themucolytic action upon sperm as well as vaginal and cervical mucous,allowing the spermicide to reach the sperm better. The cleansing andanti-inflammatory, antibioticenhancing, fibrinolytic, mucolytic, anddebriding properties of such enzymes is known. Thus, they can be used invehicles of the present invention for intravaginal infestations such asvaginitis, leukorrhea, trichomonas, moniliasis, as well as for hygienicand prophylactic purposes by incorporating them alone or in combinationwith suitable antiseptics, germicides, antibiotics, and peptizing agentssuch as carbamide. Water has been omitted in Examples 13 through 16 toincrease the stability of the enzymes and antibiotics. Stability studieshave shown that enzymes retain over 50% of their proteolytic activityagainst standard substrates when left at room temperature for sixmonths.

Propylene glycol U.S.P. q.s. ad 100 This combination was formulated forinstances where a contraceptive is desired in combination withtrichomonal or other antibiotic or where the latter is desired alone inan aerosol foam treatment. It is known that Tyrothricin andChlortetracycline are more active protozoal agents than streptomycin,chloramphenicol, or penicillin. Tyrothricin possesses many advantagesover other antibiotics for use in the vehicle of the present invention.It is odorless and has remarkable stability, being stable in aqueoussolutions and propylene glycol for long periods even at summertemperatures. Its solution in propylene glycol may be autoclaved withoutsignificant loss of activity. Its solubility in propylene glycol and itscompatibility with many organic and inorganic substances makes ituniquely useful with a spermicidal composition. Lactic acid has beenadded to this composition to maintain a healthier flora in the vagina.As is known, the treatment of trichomonas vaginalis is directed towardcleanliness and maintenance of acid pH in the vagina. Water has beenadded to the formula to aid in the ionization of the acid.

EXAMPLE l8 Grams Aliphatic polyoxyethylene ether of Example 11 5Tyrothricin 0.5 Papain 1 Vehicle of Example 7 50 Propylene glycol q.s.ad 100 can be expected in vivo that do not show in this test because ofthe enhanced action of the added enzymes and acids. No appreciabledifference in spermicidal action was noted with the addition ofantibiotics in vitro.

EXAMPLE 19 Grams Aliphatic polyoxyethylene ether of Example 11 5Hydrocortisone alcohol, micronized 1 Vehicle of Example 8 50 Propyleneglycol q.s. ad

Hydrocortisone can be used along with the contraceptive when itsanti-inflammatory action is desired. The relative insolubility and itshigh degree of activity of the alcohol form make it useful, especiallywhere the systemic effects of the glucocorticoid are not desired.

EXAMPLE 20 Grams Aliphatic polyoxyethylene ether of Example 1 5Hydrocortisone alcohol, micronized 1 Neomycin sulfate, micronized 0.5Vehicle of Example 1 50 Glycerol q.s. ad 100 This formula combines theanti-inflammatory qualities of Hydrocortisone with the anti-pyogenicaction of neomycin plus contraceptive.

EXAMPLE 21 Grams Aliphatic polyoxyethylene ether of Example 11 5Sulfanilamide, micronized 10 Vehicle of Example 1 50 Propylene glycolq.s. ad 100 Other sulfonamides may be used in place of the sulfanilamideor a combination of two or more may be used. This formula is useful inthe post-operative care of the cervix and for secondary invasions oftrichomonas vaginalis.

EXAMPLE 22 Grams Aliphatic polyoxyethylene ether of Example 11 5Sulfanilamide, micronized 10 Neomycin sulfate, micronized 0.5 Vehicle ofExample 1 50 Propylene glycol U.S.P. q.s.d. ad 100 This formula can beused when the action of a sulfonamide along with an antibiotic isdesired plus contraceptive. Another sulfonamide or sulfonamides may beused as well as antibiotics.

EXAMPLE 23 Grams Aliphatic polyoxyethylene ether of Example 11 5Povidone iodine NND 1 Vehicle of Example 1 50 Propylene glycol q.s. ad100 The addition of the iodine compound aids in the treatment ofnon-specific vaginitis and Candida albicans, Monilia, and T richomonasvaginalis along with a contraceptive.

EXAMPLE 24 Examples were prepared in accordance with each of thethirteen preceding examples (ll-23) execept that in each case thealiphatic polyoxyethylene ether was omitted.

While the particular embodiments of the present invention hereindescribed in detail are fully capable of attaining the objects andproviding the advantages hereinbefore stated, it is to be understoodthat they are merely illustrative of the presently preferred embodimentsof the invention and that no limitations are intended to the specificembodiments herein described other than as defined in the appendedclaim.

I claim:

1. A spermicidal vaginal pharmaceutical concentrate for producingnon-aqueous foam with aerosol propellants comprising:

80 grams of propylene glycol;

0.4 gram of methylhydroxyparaben;

0.2 gram of propylhydroxyparaben; I

2 grams of ethoxylated tallow alcohol containing from three to elevenmoles of ethylene oxide of the oilsoluble type; said composition ofmatter being nonaqueous, thereby constituting a stable vehicle forproteolytic enzymes and antibiotics.

References Cited UNITED STATES PATENTS 2,854,377 9/1958 Elias 167582,943,979 7/1960 Elias 167-58 3,055,834 9/1962 Charle et a1. 25290 83,131,152 4/1964 Klausner 252-305 3,219,525 11/1965 Berkow 167-583,240,396 3/ 1966 Friedenberg 222-146 3,244,589 4/ 1966 Sunnen et a1167-58 OTHER REFERENCES McCutcheon, John W.: D & E, 1963, Detergents andEmulsifiers, 1963, Annual pub., 1963, Morristown, N.J., pp.: cover,inside front cover, 31, 33, 45, 57, 58, 62, 63, 86, 87, 112, 116, 131,135.

Federal Register 30 (228): 14639 Nov. 25, 1965, Dimethyl Sulfoxide(DMSO) Preparations, Termination of Clinical Testing and InvestigationalUse.

Ferm: Teratogenic Efiect of Dimethyl Sulphoxide, Lancet, I, 1966, pp.208-209, Jan. 22, 1966.

LEWIS GOTTS, Primary Examiner.

SHEP K. ROSE, Examiner.

